The most common form of heart disease is myocardial ischemia, which is characterized by an insufficient supply of blood, substrates and oxygen to the heart due to coronary artery obstruction. If not treated, irreversible damage ensues in the form of myocardial infarction (heart attack). The overall aim of the Project is to identify mechanisms which are fundamental to the understanding of ischemic heart disease, which will be accomplished by utilizing an integrative approach including cellular and molecular studies as well as integrative whole animal physiology. This Project is based on a model of repetitive stunning in the swine, developed in the current funding period, that reproduces the chronic myocardial dysfunction with maintained viability that characterizes the human hibernating myocardium. We show in the Preliminary Data that the well defined cardioprotective mechanisms attributed to the first and second window of preconditioning are not activated in the model of repetitive stunning. Rather, in this model, cardiac protection results from the activation of a different gene/protein program of cell survival, and also from the regulation of specific intracellular pathways, including autophagy. Accordingly, this may represent a third window of protection. The goal of this proposal is to better define the mechanisms of cardioprotection activated in this model of repetitive stunning, to determine their durability, to compare those mechanisms with those activated during preconditioning, and to determine whether the repetition of ischemia extends this cardioprotection to the remote, normal myocardium. Importantly, the swine model of repetitive stunning resembles pathophysiology in humans more closely than rodents, lacks preformed coronary collateral vessels, and the heart is sufficiently large to provide measurements of regional function, blood flow, biochemistry, molecular biology and pathology from the same animals in both the ischemic zone and a contralateral, remote, non-ischemic zone. This project is tied closely to the other projects and cores, as well as to the major themes of the Program Project: 1)Mechanisms of myocardial ischemia and reperfusion;2)Molecular signaling; 3)Myocardial protection and cell survival vs. cell death;4)lntegrative cardiovascular research. This project is linked closely to Project 1, which also studies the chronically instrumented swine model, but in Project 1 the model is one of regional cardiac denervation. Indeed, several of the aims are shared by Projects 1 and 2, using two different models. It will be critical to compare the cellular/molecular alterations in Projects 1 and 2 to derive an understanding of the differences between the second and potentially, third window of protection. Project 2 interacts with Project 3 in terms of molecular signaling and mechanisms of apoptosis, and with Project 4 particularly related to H11 kinase and its role in the protection afforded by chronic, repetitive stunning. Project 2 also utilizes all of the Cores.